Analysis module 2: Maternal antibodies, study arm, and inflammatory markers by country and ORV response RoVI study — 20 July, 2021

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Methods

Shedding by country/arm

Immunogenicity by country/arm

RV-IgA vs cumulative shedding

Maternal Abs by country/arm/exposure

Maternal Abs vs ORV outcome

EED biomarkers by country/arm/exposure

EED biomarkers vs ORV outcome

Neonatal exposure vs ORV outcome

Session info

Methods

Comparisons by country/arm

  • For binary covariates (seroconversion, shedding, etc), comparisons are pairwise Fisher’s exact tests with FDR adjustment.
  • For continuous covariates (titre, inflammatory markers, etc), comparisons are ANOVAs of log-transformed values with post-hoc Tukey tests.
  • * p <0.05; ** p <0.005; *** p <0.0005.

Comparisons by ORV outcome

  • For binary endpoints (seroconversion/shedding), comparisons are logistic regressions.
  • For continuous endpoint (post-vaccination RV-IgA), comparisons are linear regressions of log-transformed RV-IgA concentration.
  • See Module 5 for full univariate and multivariate analyses of ORV outcome.
  • * p <0.05; ** p <0.005; *** p <0.0005.

Shedding by country/arm

Column

Country

Summary of sample sizes

      n neonatal_shedding dose1_shedding dose2_shedding either_shedding
IND 307               306            305            306             304
MLW 119               102            101             83              72
UK   60                58             60             56              56
    seroconv any_response
IND      305          302
MLW      103           61
UK        51           48

ORV shedding

Neonatal and vaccine shedding

Raw data and p values

Neonatal shedding
  proportions positive   n percent
1         IND      136 306    44.4
2         MLW        6 102     5.9
3          UK        1  58     1.7
    p_values      p
1 IND vs MLW 0.0000
2  IND vs UK 0.0000
3  MLW vs UK 0.4235
Dose 1 shedding
  proportions positive   n percent
1         IND       82 305    26.9
2         MLW       56 101    55.4
3          UK       55  60    91.7
    p_values      p
1 IND vs MLW 0.0000
2  IND vs UK 0.0000
3  MLW vs UK 0.0000
Dose 2 shedding
  proportions positive   n percent
1         IND       91 306    29.7
2         MLW       33  83    39.8
3          UK       35  56    62.5
    p_values      p
1 IND vs MLW 0.0860
2  IND vs UK 0.0000
3  MLW vs UK 0.0148
Shedding after either dose
  proportions positive   n percent
1         IND      151 304    49.7
2         MLW       50  72    69.4
3          UK       54  56    96.4
    p_values      p
1 IND vs MLW 0.0025
2  IND vs UK 0.0000
3  MLW vs UK 0.0001
Shedding after both doses
  proportions positive   n percent
1         IND       22 304     7.2
2         MLW       15  72    20.8
3          UK       32  56    57.1
    p_values      p
1 IND vs MLW 0.0015
2  IND vs UK 0.0000
3  MLW vs UK 0.0001
Rota shedding (VP6) by time-point

From week of life 6 onwards, +2 weeks in the UK owing to later oral rotavirus vaccine schedule.

Raw data and p values

Maternal (MS1)
  proportions positive   n percent
1         IND        2 307     0.7
2         MLW        1  96     1.0
3          UK        2  58     3.4
    p_values      p
1 IND vs MLW 0.5590
2  IND vs UK 0.3610
3  MLW vs UK 0.5590
Week 1 (BS1)
  proportions positive   n percent
1         IND      136 306    44.4
2         MLW        6 102     5.9
3          UK        1  58     1.7
    p_values      p
1 IND vs MLW 0.0000
2  IND vs UK 0.0000
3  MLW vs UK 0.4235
Week 4 (BS2)
  proportions positive   n percent
1         IND        0 305     0.0
2         MLW        3  91     3.3
3          UK        4  57     7.0
    p_values      p
1 IND vs MLW 0.0177
2  IND vs UK 0.0017
3  MLW vs UK 0.4296
Week 6/8 (BS3)
  proportions positive   n percent
1         IND        2 305     0.7
2         MLW        5  88     5.7
3          UK       10  51    19.6
    p_values      p
1 IND vs MLW 0.0110
2  IND vs UK 0.0000
3  MLW vs UK 0.0203
Week 7/9 (BS4)
  proportions positive   n percent
1         IND       43 307    14.0
2         MLW       36  80    45.0
3          UK       49  59    83.1
    p_values      p
1 IND vs MLW 0.0000
2  IND vs UK 0.0000
3  MLW vs UK 0.0000
Week 10/12 (BS5)
  proportions positive   n percent
1         IND        8 304     2.6
2         MLW        9  79    11.4
3          UK       24  54    44.4
    p_values      p
1 IND vs MLW 0.0026
2  IND vs UK 0.0000
3  MLW vs UK 0.0000
Week 11/13 (BS6)
  proportions positive   n percent
1         IND       37 306    12.1
2         MLW       18  84    21.4
3          UK       29  55    52.7
    p_values      p
1 IND vs MLW 0.0345
2  IND vs UK 0.0000
3  MLW vs UK 0.0003
Number of infants with birth shedding, dose 1 shedding, dose 2 shedding and post-vaccination IgA

IND MLW  UK 
301  53  50

Minimum NSP2 Ct among ORV shedders

P values (pairwise Wilcoxon tests with FDR correction)

     comp            p          fdr
1 IND-MLW 4.995433e-03 7.493149e-03
2  UK-MLW 2.664895e-01 2.664895e-01
3  IND-UK 4.574514e-06 1.372354e-05

Arm

Summary of sample sizes

            n neonatal_shedding dose1_shedding dose2_shedding either_shedding
IND (IPV) 100                99             99             99              98
IND (OPV) 207               207            206            207             206
          seroconv any_response
IND (IPV)       99           97
IND (OPV)      206          205
Neonatal and vaccine shedding

Raw data and p values

Neonatal shedding
  proportions positive   n percent
1   IND (IPV)       37  99    37.4
2   IND (OPV)       99 207    47.8
                    p_values      p
1 India (IPV) vs India (OPV) 0.1097
Dose 1 shedding
  proportions positive   n percent
1   IND (IPV)       43  99    43.4
2   IND (OPV)       39 206    18.9
                    p_values      p
1 India (IPV) vs India (OPV) 0.0000
Dose 2 shedding
  proportions positive   n percent
1   IND (IPV)       22  99    22.2
2   IND (OPV)       69 207    33.3
                    p_values      p
1 India (IPV) vs India (OPV) 0.0609
Shedding after either dose
  proportions positive   n percent
1   IND (IPV)       54  98    55.1
2   IND (OPV)       97 206    47.1
                    p_values      p
1 India (IPV) vs India (OPV) 0.2201
Shedding after both doses
  proportions positive   n percent
1   IND (IPV)       11  98    11.2
2   IND (OPV)       11 206     5.3
                    p_values      p
1 India (IPV) vs India (OPV) 0.0947
Rota shedding (VP6) by time-point

Raw data and p values

Maternal (MS1)
  proportions positive   n percent
1   IND (IPV)        1 100     1.0
2   IND (OPV)        1 207     0.5
                    p_values      p
1 India (IPV) vs India (OPV) 0.5461
Week 1 (BS1)
  proportions positive   n percent
1   IND (IPV)       37  99    37.4
2   IND (OPV)       99 207    47.8
                    p_values      p
1 India (IPV) vs India (OPV) 0.1097
Week 4 (BS2)

Not applicable - no shedding observed in IPV arm or OPV arm in week-4 samples.

Week 6/8 (BS3)
  proportions positive   n percent
1   IND (IPV)        0 100       0
2   IND (OPV)        2 205       1
                    p_values      p
1 India (IPV) vs India (OPV) 1.0000
Week 7/9 (BS4)
  proportions positive   n percent
1   IND (IPV)       23 100    23.0
2   IND (OPV)       20 207     9.7
                    p_values      p
1 India (IPV) vs India (OPV) 0.0026
Week 10/12 (BS5)
  proportions positive   n percent
1   IND (IPV)        6  99     6.1
2   IND (OPV)        2 205     1.0
                    p_values      p
1 India (IPV) vs India (OPV) 0.0162
Week 11/13 (BS6)
  proportions positive   n percent
1   IND (IPV)        6  99     6.1
2   IND (OPV)       31 207    15.0
                    p_values      p
1 India (IPV) vs India (OPV) 0.0251
Number of infants with birth shedding, dose 1 shedding, dose 2 shedding and post-vaccination IgA

IND (IPV) IND (OPV) 
       96       205

Minimum NSP2 Ct among ORV shedders

P value (pairwise Wilcoxon test)

     comp         p
1 OPV-IPV 0.4338797

Immunogenicity by country/arm

Column

Country

ORV immunogenicity - seroconversion and RV-IgA

ORV immunogenicity - seropositivity pre- and post-ORV

Raw data and p values

Seroconversion
  proportions positive   n percent
1         IND       85 305    27.9
2         MLW       24 103    23.3
3          UK       27  51    52.9
    p_values      p
1 IND vs MLW 0.4398
2  IND vs UK 0.0009
3  MLW vs UK 0.0009
Seropositivity, pre-ORV
  proportions positive   n percent
1         IND       99 305    32.5
2         MLW        5 103     4.9
3          UK        2  56     3.6
    p_values      p
1 IND vs MLW 0.0000
2  IND vs UK 0.0000
3  MLW vs UK 1.0000
Seropositivity, post-ORV
  proportions positive   n percent
1         IND      154 305    50.5
2         MLW       26 103    25.2
3          UK       30  54    55.6
    p_values      p
1 IND vs MLW 0.0000
2  IND vs UK 0.5556
3  MLW vs UK 0.0003
Infant RV-IgA pre-vaccination
  gmts   n mean lwr.ci upr.ci
1  IND 305 7.53   6.09   9.31
2  MLW 103 3.25   2.66   3.99
3   UK  56 2.65   1.96   3.59
    p_values      p
1 IND vs MLW 0.0000
2  IND vs UK 0.0001
3  MLW vs UK 0.7334
Infant RV-IgA post-vaccination
  gmts   n  mean lwr.ci upr.ci
1  IND 305 19.80  15.76  24.88
2  MLW 103  8.85   6.28  12.47
3   UK  54 27.47  16.89  44.68
    p_values      p
1 IND vs MLW 0.0009
2  IND vs UK 0.4886
3  MLW vs UK 0.0016
Seropositivity by neonatal infection status in India
   
      0   1
  0 138  31
  1  67  68

Pre-vaccination exposure by country (either seropositivity or week-1 shedding)

   
    IND MLW  UK
  0 138  80  52
  1 166  10   2

ORV immunogenicity - final RV-IgA in seroconverters

Infant RV-IgA post-vaccination
  gmts  n   mean lwr.ci upr.ci
1  IND 85  92.94  73.02 118.31
2  MLW 24 122.38  79.99 187.24
3   UK 27 105.11  71.13 155.33
    p_values      p
1 IND vs MLW 0.5115
2  IND vs UK 0.8627
3  MLW vs UK 0.8694

Arm

ORV immunogenicity

ORV immunogenicity - seropositivity pre- and post-ORV

Raw data and p values

Seroconversion
  proportions positive   n percent
1   IND (IPV)       25  99    25.3
2   IND (OPV)       60 206    29.1
                    p_values      p
1 India (IPV) vs India (OPV) 0.4990
Seropositivity, pre-ORV
  proportions positive   n percent
1   IND (IPV)       27  99    27.3
2   IND (OPV)       72 206    35.0
                    p_values      p
1 India (IPV) vs India (OPV) 0.1937
Seropositivity, post-ORV
  proportions positive   n percent
1   IND (IPV)       47  99    47.5
2   IND (OPV)      107 206    51.9
                    p_values      p
1 India (IPV) vs India (OPV) 0.5410
Infant RV-IgA pre-vaccination
       gmts   n  mean lwr.ci upr.ci
1 IND (IPV)  99  6.02   4.14   8.74
2 IND (OPV) 206  8.38   6.47  10.87
                p_values      p
1 IND (IPV) vs IND (OPV) 0.1503
Infant RV-IgA post-vaccination
       gmts   n  mean lwr.ci upr.ci
1 IND (IPV)  99 16.88  11.48  24.82
2 IND (OPV) 206 21.37  16.08  28.41
                p_values      p
1 IND (IPV) vs IND (OPV) 0.3423

RV-IgA vs cumulative shedding

Column

Number of infants with birth shedding, dose 1 shedding, dose 2 shedding, pre-vaccination IgA and post-vaccination IgA

IND MLW  UK 
301  53  47

Cumulative effect of birth exposure and vaccination on IgA titre

Exposure defined as week-1 shedding or IgA positivity pre-vaccination. Shedding subgroups with <5 infants excluded. 
     
      -- -+ +- ++
  IND 53 84 99 65
  MLW 16 33  2  2
  UK   2 44  0  1

P values

India
$`s1I$shedding_group`
           diff         lwr       upr        p adj
-+--- 0.2517953 -0.07304050 0.5766310 1.892829e-01
+---- 0.9803076  0.66513578 1.2954794 1.041944e-12
++--- 1.3756276  1.03291698 1.7183382 9.058310e-13
+---+ 0.7285123  0.45381817 1.0032065 2.530073e-10
++--+ 1.1238323  0.81793338 1.4297312 9.047207e-13
++-+- 0.3953200  0.09970339 0.6909365 3.510221e-03
Malawi
$`s1M$shedding_group`
           diff       lwr       upr       p adj
-+--- 0.4989606 0.1278144 0.8701068 0.009495288

Maternal Abs by country/arm/exposure

Column

Country

Number of Indian infants with MB IgA, MB IgG, CB IgG, BB1 IgG and no pre-vaccination RV exposure

[1] 138

Pearson’s correlation coefficient for MB RV-IgA and MB RV-IgG (log transformed)


    Pearson's product-moment correlation

data:  log(t$MB1_IgA) and log(t$MB1_IgG)
t = 8.254, df = 136, p-value = 1.185e-13
alternative hypothesis: true correlation is not equal to 0
95 percent confidence interval:
 0.4544851 0.6792457
sample estimates:
      cor 
0.5777145

Pearson’s correlation coefficient for MB RV-IgA and BM RV-IgA (log transformed)


    Pearson's product-moment correlation

data:  log(t$MB1_IgA) and log(t$BM1_IgA)
t = 2.7965, df = 135, p-value = 0.005921
alternative hypothesis: true correlation is not equal to 0
95 percent confidence interval:
 0.06899184 0.38654509
sample estimates:
      cor 
0.2339997

Maternal IgA antibody levels

Raw data and p values

Maternal RV-IgA
  gmts   n   mean lwr.ci upr.ci
1  IND 305 134.02 119.58 150.21
2  MLW 103 340.29 256.31 451.77
3   UK  49 186.05 123.33 280.67
    p_values      p
1 IND vs MLW 0.0000
2  IND vs UK 0.1649
3  MLW vs UK 0.0089
Breastmilk RV-IgA
  gmts   n   mean lwr.ci upr.ci
1  IND 301  25.28  21.98  29.08
2  MLW  78  96.98  83.66 112.42
3   UK  30  99.64  68.19 145.58
    p_values      p
1 IND vs MLW 0.0000
2  IND vs UK 0.0000
3  MLW vs UK 0.9932
Serum/breastmilk RV-IgA ratio
  gmts   n mean lwr.ci upr.ci
1  IND 301 0.62   0.59   0.66
2  MLW  78 0.86   0.76   0.98
3   UK  26 0.96   0.78   1.18
  Comparison         Z      P.unadj        P.adj
1  IND - MLW -5.994695 2.038676e-09 6.116028e-09
2   IND - UK -5.157198 2.506725e-07 3.760087e-07
3   MLW - UK -1.291804 1.964250e-01 1.964250e-01

Arm

Antibody levels

Raw data and p values

Maternal RV-IgA
       gmts   n   mean lwr.ci upr.ci
1 IND (IPV)  99 151.37 123.00 186.29
2 IND (OPV) 206 126.41 110.26 144.92
                p_values      p
1 IND (IPV) vs IND (OPV) 0.1456
Breastmilk RV-IgA
       gmts   n  mean lwr.ci upr.ci
1 IND (IPV)  99 25.77  20.00  33.20
2 IND (OPV) 202 25.05  21.15  29.66
                p_values      p
1 IND (IPV) vs IND (OPV) 0.8516
Maternal RV-IgG
       gmts   n     mean   lwr.ci   upr.ci
1 IND (IPV)  99 11150.25  9184.84 13536.24
2 IND (OPV) 206  9538.78  8318.17 10938.50
                p_values      p
1 IND (IPV) vs IND (OPV) 0.1978
Cord-blood RV-IgG
       gmts   n     mean   lwr.ci   upr.ci
1 IND (IPV)  99 15481.74 12986.50 18456.41
2 IND (OPV) 206 13189.67 11435.85 15212.45
                p_values      p
1 IND (IPV) vs IND (OPV) 0.1869

Exposure status

Antibody levels

Raw data and p values

Maternal RV-IgA
        gmts   n   mean lwr.ci upr.ci
1 IND (neo-) 138 131.05 113.21 151.70
2 IND (neo+) 166 137.90 114.93 165.47
                  p_values      p
1 IND (neo+) vs IND (neo-) 0.6633
Breastmilk RV-IgA
        gmts   n  mean lwr.ci upr.ci
1 IND (neo-) 137 23.65  19.69  28.40
2 IND (neo+) 163 27.61  22.20  34.34
                  p_values      p
1 IND (neo+) vs IND (neo-) 0.2795
Maternal RV-IgG
        gmts   n     mean   lwr.ci   upr.ci
1 IND (neo-) 138  9642.07  8304.85 11194.61
2 IND (neo+) 166 10475.81  8834.78 12421.66
                  p_values      p
1 IND (neo+) vs IND (neo-) 0.4684
Cord-blood RV-IgG
        gmts   n     mean   lwr.ci   upr.ci
1 IND (neo-) 138 13497.15 11761.34 15489.13
2 IND (neo+) 166 14278.52 11873.36 17170.88
                  p_values      p
1 IND (neo+) vs IND (neo-) 0.6230

Maternal Abs vs ORV outcome

Column

Summary

See Module 5 for full univariate and multivariate analyses.

Correlation networks

India

Correlation between of MB1 IgA and CB IgG


    Pearson's product-moment correlation

data:  log(s_sub$MB1_IgA) and log(s_sub$CB1_IgG)
t = 7.8633, df = 303, p-value = 6.625e-14
alternative hypothesis: true correlation is not equal to 0
95 percent confidence interval:
 0.3138832 0.5008302
sample estimates:
      cor 
0.4116784

Correlation between of MB1 IgA and BM IgA


    Pearson's product-moment correlation

data:  log(s_sub$MB1_IgA) and log(s_sub$BM1_IgA)
t = 5.3282, df = 299, p-value = 1.955e-07
alternative hypothesis: true correlation is not equal to 0
95 percent confidence interval:
 0.1876722 0.3943989
sample estimates:
      cor 
0.2944767

Full correlation network

Number with complete antibody data = 298

India (exposed subset)

Number with complete antibody data = 161

India (unexposed subset)

Number with complete antibody data = 137

Malawi

Full correlation network

Correlation between of MB1 IgA and BM IgA


    Pearson's product-moment correlation

data:  log(s_sub$MB1_IgA) and log(s_sub$BM1_IgA)
t = 3.6458, df = 76, p-value = 0.0004855
alternative hypothesis: true correlation is not equal to 0
95 percent confidence interval:
 0.1786308 0.5602533
sample estimates:
      cor 
0.3858247

Number with complete antibody data = 64

UK

Full correlation network

Number with complete antibody data = 42 (breastmilk IgA data excluded as this reduced the number of complete cases from 40 to 22).

Correlation between of MB1 IgA and BM IgA


    Pearson's product-moment correlation

data:  log(s_sub$MB1_IgA) and log(s_sub$BM1_IgA)
t = 1.4668, df = 24, p-value = 0.1554
alternative hypothesis: true correlation is not equal to 0
95 percent confidence interval:
 -0.1130915  0.6067642
sample estimates:
      cor 
0.2868252

Continuous outcomes

Pearson correlation coefficients: maternal antibodies vs pre-vaccination RV-IgA

Pearson correlation coefficients
           India_exposed
MB1 RV-IgA       -0.1500
BM1 RV-IgA       -0.1191
BB1 RV-IgA        1.0000
MB1 RV-IgG       -0.4216
CB1 RV-IgG       -0.3843
BB1 RV-IgG        0.2170
P values
           India_exposed
MB1 RV-IgA        0.0537
BM1 RV-IgA        0.1298
BB1 RV-IgA        0.0000
MB1 RV-IgG        0.0000
CB1 RV-IgG        0.0000
BB1 RV-IgG        0.0050

Pearson correlation coefficients: maternal antibodies vs post-vaccination RV-IgA

Pearson correlation coefficients
             India India_neo_pos India_neo_neg  Malawi      UK
MB1 RV-IgA -0.1298       -0.1816       -0.0930 -0.2884 -0.1168
BM1 RV-IgA -0.1367       -0.1077       -0.1599 -0.2594  0.1924
BB1 RV-IgA  0.7479        0.6888        0.4549  0.4132  0.3303
MB1 RV-IgG -0.2608       -0.3711       -0.1644      NA      NA
CB1 RV-IgG -0.2109       -0.3291       -0.1209      NA      NA
BB1 RV-IgG  0.1027        0.0136       -0.1134      NA      NA
P values
            India India_neo_pos India_neo_neg Malawi     UK
MB1 RV-IgA 0.0234        0.0192        0.2782 0.0031 0.4446
BM1 RV-IgA 0.0176        0.1710        0.0619 0.0218 0.3175
BB1 RV-IgA 0.0000        0.0000        0.0000 0.0000 0.0179
MB1 RV-IgG 0.0000        0.0000        0.0540     NA     NA
CB1 RV-IgG 0.0002        0.0000        0.1579     NA     NA
BB1 RV-IgG 0.0734        0.8617        0.1856     NA     NA
N
  India India_neo_pos India_neo_neg Malawi UK
1   305           166           138    103 45
2   301           163           137     78 29
3   305           166           138    103 51
4   305           166           138     NA NA
5   305           166           138     NA NA
6   305           166           138     NA NA

Effect modification

Model for final RV-IgA vs MB RV-IgA + country


Call:
lm(formula = log(BB2_IgA) ~ log(MB1_IgA) + country, data = s)

Residuals:
    Min      1Q  Median      3Q     Max 
-3.9242 -1.5926 -0.0985  1.4952  5.3765 

Coefficients:
             Estimate Std. Error t value Pr(>|t|)    
(Intercept)   4.32175    0.39380  10.975  < 2e-16 ***
log(MB1_IgA) -0.27278    0.07719  -3.534 0.000452 ***
countryMLW   -0.55130    0.23086  -2.388 0.017352 *  
countryUK     0.43999    0.30847   1.426 0.154453    
---
Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1

Residual standard error: 1.925 on 449 degrees of freedom
  (33 observations deleted due to missingness)
Multiple R-squared:  0.06128,   Adjusted R-squared:  0.05501 
F-statistic: 9.771 on 3 and 449 DF,  p-value: 2.956e-06

Model with interaction terms


Call:
lm(formula = log(BB2_IgA) ~ log(MB1_IgA) * factor(country), data = s)

Residuals:
    Min      1Q  Median      3Q     Max 
-3.8672 -1.5512 -0.1094  1.4675  5.3505 

Coefficients:
                                Estimate Std. Error t value Pr(>|t|)    
(Intercept)                      4.25958    0.54646   7.795 4.57e-14 ***
log(MB1_IgA)                    -0.26009    0.10927  -2.380   0.0177 *  
factor(country)MLW              -0.04537    0.96101  -0.047   0.9624    
factor(country)UK               -0.16984    1.19857  -0.142   0.8874    
log(MB1_IgA):factor(country)MLW -0.08881    0.17107  -0.519   0.6039    
log(MB1_IgA):factor(country)UK   0.11579    0.22476   0.515   0.6067    
---
Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1

Residual standard error: 1.928 on 447 degrees of freedom
  (33 observations deleted due to missingness)
Multiple R-squared:  0.06291,   Adjusted R-squared:  0.05243 
F-statistic: 6.001 on 5 and 447 DF,  p-value: 2.177e-05

Comparison of fit

Analysis of Variance Table

Model 1: log(BB2_IgA) ~ log(MB1_IgA) + country
Model 2: log(BB2_IgA) ~ log(MB1_IgA) * factor(country)
  Res.Df    RSS Df Sum of Sq      F Pr(>F)
1    449 1663.8                           
2    447 1660.9  2    2.8825 0.3879 0.6787

India vs Malawi

Analysis of Variance Table

Model 1: log(BB2_IgA) ~ log(MB1_IgA) + factor(country)
Model 2: log(BB2_IgA) ~ log(MB1_IgA) * factor(country)
  Res.Df  RSS Df Sum of Sq      F Pr(>F)
1    405 1517                           
2    404 1516  1    1.0014 0.2669 0.6057

UK vs India/Malawi

Analysis of Variance Table

Model 1: log(BB2_IgA) ~ log(MB1_IgA) + factor(country == "UK")
Model 2: log(BB2_IgA) ~ log(MB1_IgA) * factor(country == "UK")
  Res.Df    RSS Df Sum of Sq      F Pr(>F)
1    450 1684.9                           
2    449 1681.0  1    3.8696 1.0336 0.3099

Exposure status (within in India)

Analysis of Variance Table

Model 1: log(BB2_IgA) ~ log(MB1_IgA) + factor(pre_exposed)
Model 2: log(BB2_IgA) ~ log(MB1_IgA) * factor(pre_exposed)
  Res.Df    RSS Df Sum of Sq      F Pr(>F)
1    301 846.95                           
2    300 843.40  1    3.5517 1.2633 0.2619

No significant evidence that the association between maternal RV-IgA and infant post-vaccination RV-IgA differs by country or between high-income settings (UK) vs LMICs (India/Malawi).

EED biomarkers by country/arm/exposure

Column

Country

EED biomarker levels

Raw data and p values

α1AT (week 6/8)
  gmts   n    mean  lwr.ci  upr.ci
1  IND 301  733.73  676.02  796.37
2  MLW  83 4375.69 3136.03 6105.37
3   UK  48  281.91  155.44  511.28
    p_values      p
1 IND vs MLW 0.0000
2  IND vs UK 0.0000
3  MLW vs UK 0.0000
MPO (week 6/8)
  gmts   n    mean  lwr.ci  upr.ci
1  IND 301 6463.46 5445.64 7671.52
2  MLW  83 2965.95 2454.03 3584.65
3   UK  47 3766.08 2412.79 5878.40
    p_values      p
1 IND vs MLW 0.0000
2  IND vs UK 0.0399
3  MLW vs UK 0.6234
α1AG (week 6)
  gmts   n  mean lwr.ci upr.ci
1  IND 304 722.8  702.8  743.5
2  MLW  87   519  454.1  593.3
$`t$country`
              diff        lwr        upr p adj
MLW-IND -0.3312002 -0.4191556 -0.2432447     0
α1AT (week 10/12)
  gmts   n     mean   lwr.ci   upr.ci
1  IND 298   820.02   742.48   905.65
2  MLW  63  9221.87  6642.43 12802.97
3   UK  51   507.69   337.76   763.13
    p_values      p
1 IND vs MLW 0.0000
2  IND vs UK 0.0065
3  MLW vs UK 0.0000
MPO (week 10/12)
  gmts   n    mean  lwr.ci  upr.ci
1  IND 298 7327.25 6193.44 8668.61
2  MLW  63 4134.60 3098.09 5517.89
3   UK  51 3082.37 1974.36 4812.20
    p_values      p
1 IND vs MLW 0.0124
2  IND vs UK 0.0003
3  MLW vs UK 0.5271

Arm

Raw data and p values

α1AT (week 6)
       gmts   n   mean lwr.ci upr.ci
1 IND (IPV)  97 759.18 650.11 886.54
2 IND (OPV) 202 719.45 652.68 793.04
                p_values      p
1 IND (IPV) vs IND (OPV) 0.5486
MPO (week 6)
       gmts   n    mean  lwr.ci  upr.ci
1 IND (IPV)  97 5291.23 3901.62 7175.75
2 IND (OPV) 202 7040.60 5711.91 8678.36
                p_values      p
1 IND (IPV) vs IND (OPV) 0.1264
α1AG (week 6)
       gmts   n   mean lwr.ci upr.ci
1 IND (IPV)  98 707.87 672.84 744.71
2 IND (OPV) 205 729.80 705.28 755.16
                p_values      p
1 IND (IPV) vs IND (OPV) 0.3207
α1AT (week 10)
       gmts   n   mean lwr.ci upr.ci
1 IND (IPV)  96 794.26 673.12 937.22
2 IND (OPV) 200 829.23 731.31 940.25
                p_values      p
1 IND (IPV) vs IND (OPV) 0.6920
MPO (week 10)
       gmts   n    mean  lwr.ci  upr.ci
1 IND (IPV)  96 7072.33 5319.52 9402.70
2 IND (OPV) 200 7597.93 6160.52 9370.73
                p_values      p
1 IND (IPV) vs IND (OPV) 0.6954

Exposure status

Raw data and p values

α1AT (week 6)
        gmts   n   mean lwr.ci upr.ci
1 IND (neo-) 136 713.51 638.96 796.76
2 IND (neo+) 163 755.02 666.28 855.59
                  p_values      p
1 IND (neo+) vs IND (neo-) 0.5020
MPO (week 6)
        gmts   n    mean  lwr.ci  upr.ci
1 IND (neo-) 136 6364.62 5042.66 8033.13
2 IND (neo+) 163 6481.43 5003.58 8395.77
                  p_values      p
1 IND (neo+) vs IND (neo-) 0.9177
α1AG (week 6)
        gmts   n   mean lwr.ci upr.ci
1 IND (neo-) 138 713.85 686.98 741.77
2 IND (neo+) 165 733.27 703.05 764.79
                  p_values      p
1 IND (neo+) vs IND (neo-) 0.3524
α1AT (week 10)
        gmts   n    mean  lwr.ci  upr.ci
1 IND (neo-) 134  770.88  667.28  890.56
2 IND (neo+) 162  878.17  766.32 1006.35
                  p_values      p
1 IND (neo+) vs IND (neo-) 0.2020
MPO (week 10/12)
        gmts   n     mean   lwr.ci   upr.ci
1 IND (neo-) 134  6610.54  5233.69  8349.60
2 IND (neo+) 162  8540.50  6699.34 10887.65
                  p_values      p
1 IND (neo+) vs IND (neo-) 0.1361

EED biomarkers vs ORV outcome

Summary

See Module 5 for full univariate and multivariate analyses.

Continuous outcomes

Pearson correlation coefficients: EED markers vs pre-vaccination RV-IgA

Pearson correlation coefficients
               India_neo_pos
α1AT (week 6)         0.0581
α1AT (week 10)       -0.0204
MPO (week 6)          0.1368
MPO (week 10)         0.0387
α1AG (week 6)         0.0306
P values
               India_neo_pos
α1AT (week 6)         0.4617
α1AT (week 10)        0.7965
MPO (week 6)          0.0817
MPO (week 10)         0.6252
α1AG (week 6)         0.6967
N
  India
1   163
2   162
3   163
4   162
5   165

Pearson correlation coefficients: EED vs post-vaccination RV-IgA

Pearson correlation coefficients
                         India India_neo_pos India_neo_neg  Malawi      UK
α1AT (week of life 6)  -0.0325        0.0597       -0.0996 -0.0601 -0.0815
α1AT (week of life 10) -0.0624       -0.0298       -0.0102  0.0835  0.2202
MPO (week of life 6)   -0.0294        0.0343       -0.1183 -0.0318 -0.0388
MPO (week of life 10)  -0.1112       -0.0618       -0.1239  0.0242 -0.2363
α1AG (week of life 6)  -0.0818       -0.1074        0.0041 -0.0230      NA
P values
                        India India_neo_pos India_neo_neg Malawi     UK
α1AT (week of life 6)  0.5748        0.4489        0.2485 0.6013 0.6036
α1AT (week of life 10) 0.2836        0.7064        0.9069 0.5521 0.1325
MPO (week of life 6)   0.6125        0.6641        0.1702 0.7824 0.8072
MPO (week of life 10)  0.0556        0.4347        0.1538 0.8637 0.1138
α1AG (week of life 6)  0.1546        0.1699        0.9617 0.8327     NA
N
  India India_neo_pos India_neo_neg Malawi UK
1   300           163           136     78 43
2   297           162           134     53 48
3   300           163           136     78 42
4   297           162           134     53 46
5   304           165           138     87 NA

Neonatal exposure vs ORV outcome

Column

Pre-exposure by cohort

   
    IND MLW  UK
  0 138  80  52
  1 166  10   2

Pre-exposure defined as detection of week-1 shedding (VP6 Ct <35) or seropositivity pre-vaccination (RV-IgA ≥20 IU/ml)

ORV response by exposure status (with Malawi and UK as comparison groups)

Raw data and p values

Dose 1 shedding
  proportions positive   n percent     p
1  IND (neo-)       52 138    37.7 1e-04
2  IND (neo+)       29 164    17.7    NA
Shedding of either dose
  proportions positive   n percent     p
1  IND (neo-)       84 137    61.3 2e-04
2  IND (neo+)       65 164    39.6    NA
Seroconversion
  proportions positive   n percent      p
1  IND (neo-)       34 138    24.6 0.2508
2  IND (neo+)       51 166    30.7     NA
Pre-ORV RV-IgA
       group mean lwr.ci upr.ci  p
1 IND (neo-)  1.9    1.7    2.2  0
2 IND (neo+) 23.7   18.1   31.1 NA
Post-ORV RV-IgA
       group mean lwr.ci upr.ci  p
1 IND (neo-)  5.9    4.6    7.6  0
2 IND (neo+) 55.1   41.8   72.8 NA

Session info

R version 3.6.1 (2019-07-05)
Platform: x86_64-apple-darwin15.6.0 (64-bit)
Running under: macOS  10.16

Matrix products: default
BLAS:   /Library/Frameworks/R.framework/Versions/3.6/Resources/lib/libRblas.0.dylib
LAPACK: /Library/Frameworks/R.framework/Versions/3.6/Resources/lib/libRlapack.dylib

locale:
[1] en_GB.UTF-8/en_GB.UTF-8/en_GB.UTF-8/C/en_GB.UTF-8/en_GB.UTF-8

attached base packages:
[1] parallel  stats4    stats     graphics  grDevices utils     datasets 
[8] methods   base     

other attached packages:
 [1] FSA_0.9.0                   ALDEx2_1.18.0              
 [3] sjstats_0.18.0              ggExtra_0.9                
 [5] formattable_0.2.0.1         NBZIMM_1.0                 
 [7] inlmisc_0.5.2               decontam_1.6.0             
 [9] ggtree_2.0.4                wesanderson_0.3.6          
[11] phangorn_2.5.5              ape_5.4-1                  
[13] DECIPHER_2.14.0             RSQLite_2.2.1              
[15] Biostrings_2.54.0           XVector_0.26.0             
[17] cowplot_1.1.0               scales_1.1.1               
[19] RVAideMemoire_0.9-78        DescTools_0.99.38          
[21] ggsignif_0.6.0              binom_1.1-1                
[23] shiny_1.5.0                 randomcoloR_1.1.0.1        
[25] DESeq2_1.26.0               SummarizedExperiment_1.16.1
[27] DelayedArray_0.12.3         BiocParallel_1.20.1        
[29] Biobase_2.46.0              GenomicRanges_1.38.0       
[31] GenomeInfoDb_1.22.1         IRanges_2.20.2             
[33] S4Vectors_0.24.4            BiocGenerics_0.32.0        
[35] crossval_1.0.3              UpSetR_1.4.0               
[37] labdsv_2.0-1                mgcv_1.8-33                
[39] nlme_3.1-149                ggpubr_0.4.0               
[41] data.table_1.12.8           corrplot_0.84              
[43] ZIBR_0.1                    vegan_2.5-6                
[45] lattice_0.20-41             permute_0.9-5              
[47] randomForest_4.6-14         matrixStats_0.57.0         
[49] lme4_1.1-23                 Matrix_1.2-18              
[51] reshape2_1.4.4              pheatmap_1.0.12            
[53] DT_0.16                     plotly_4.9.3               
[55] cluster_2.1.0               tidyr_1.1.2                
[57] dplyr_1.0.2                 magrittr_1.5               
[59] plyr_1.8.6                  kableExtra_1.2.1           
[61] gridExtra_2.3               RColorBrewer_1.1-2         
[63] knitr_1.30                  ggplot2_3.3.2              
[65] phyloseq_1.30.0            

loaded via a namespace (and not attached):
  [1] estimability_1.3       coda_0.19-4            bit64_4.0.5           
  [4] rpart_4.1-15           RCurl_1.98-1.2         generics_0.0.2        
  [7] bit_4.0.4              webshot_0.5.2          xml2_1.3.2            
 [10] httpuv_1.5.4           xfun_0.18              hms_0.5.3             
 [13] evaluate_0.14          promises_1.1.1         readxl_1.3.1          
 [16] igraph_1.2.6           DBI_1.1.0              geneplotter_1.64.0    
 [19] htmlwidgets_1.5.3      purrr_0.3.4            ellipsis_0.3.1        
 [22] backports_1.1.10       V8_3.2.0               insight_0.9.6         
 [25] annotate_1.64.0        vctrs_0.3.4            sjlabelled_1.1.7      
 [28] abind_1.4-5            withr_2.3.0            checkmate_2.0.0       
 [31] rgdal_1.5-18           emmeans_1.5.1          treeio_1.10.0         
 [34] lazyeval_0.2.2         crayon_1.3.4           flexdashboard_0.5.2   
 [37] genefilter_1.68.0      labeling_0.3           pkgconfig_2.0.3       
 [40] nnet_7.3-14            rlang_0.4.8            lifecycle_0.2.0       
 [43] miniUI_0.1.1.1         modelr_0.1.8           cellranger_1.1.0      
 [46] raster_3.3-13          carData_3.0-4          Rhdf5lib_1.8.0        
 [49] boot_1.3-25            base64enc_0.1-3        png_0.1-7             
 [52] viridisLite_0.3.0      dunn.test_1.3.5        parameters_0.8.6      
 [55] rootSolve_1.8.2.1      bitops_1.0-6           blob_1.2.1            
 [58] stringr_1.4.0          jpeg_0.1-8.1           rstatix_0.6.0         
 [61] memoise_1.1.0          zlibbioc_1.32.0        compiler_3.6.1        
 [64] ade4_1.7-15            htmlTable_2.1.0        Formula_1.2-4         
 [67] MASS_7.3-53            tidyselect_1.1.0       stringi_1.5.3         
 [70] forcats_0.5.0          yaml_2.2.1             locfit_1.5-9.4        
 [73] latticeExtra_0.6-29    grid_3.6.1             fastmatch_1.1-0       
 [76] tools_3.6.1            lmom_2.8               rio_0.5.16            
 [79] rstudioapi_0.11        foreach_1.5.1          foreign_0.8-71        
 [82] gld_2.6.2              farver_2.0.3           Rtsne_0.15            
 [85] digest_0.6.25          rvcheck_0.1.8          BiocManager_1.30.10   
 [88] quadprog_1.5-8         Rcpp_1.0.5             car_3.0-10            
 [91] broom_0.7.1            performance_0.5.0      later_1.1.0.1         
 [94] httr_1.4.2             AnnotationDbi_1.48.0   effectsize_0.3.3      
 [97] colorspace_1.4-1       rvest_0.3.6            XML_3.99-0.3          
[100] splines_3.6.1          statmod_1.4.34         tidytree_0.3.3        
[103] expm_0.999-5           sp_1.4-4               multtest_2.42.0       
[106] Exact_2.1              xtable_1.8-4           jsonlite_1.7.1        
[109] nloptr_1.2.2.2         R6_2.4.1               Hmisc_4.4-1           
[112] pillar_1.4.6           htmltools_0.5.0        mime_0.9              
[115] glue_1.4.2             fastmap_1.0.1          minqa_1.2.4           
[118] class_7.3-17           codetools_0.2-17       mvtnorm_1.1-1         
[121] tibble_3.0.4           curl_4.3               zip_2.1.1             
[124] openxlsx_4.2.2         survival_3.2-7         rmarkdown_2.4         
[127] biomformat_1.14.0      munsell_0.5.0          e1071_1.7-4           
[130] rhdf5_2.30.1           GenomeInfoDbData_1.2.2 iterators_1.0.13      
[133] sjmisc_2.8.5           haven_2.3.1            gtable_0.3.0          
[136] bayestestR_0.7.2

.